美国加州大学旧金山分校Felix Y. Feng研究小组的最新研究揭示了进展期前列腺癌DNA甲基化的情况。相关论文于2020年7月13日发表于国际学术期刊《自然-遗传学》杂志。

利用全基因组重亚硫酸氢盐测序，与对100个去势抵抗性前列腺癌转移患者进行的全基因组和转录组深度测序相结合的方法，研究人员发现了影响驱动基因的改变，这些改变只有通过整合全基因组方法才能检测到。值得注意的是，研究人员观察到22％的肿瘤在TET2、DNMT3B、IDH1和BRAF中表现出与甲基化和体细胞突变有关的新型表观基因组亚型。

研究人员还确定了甲基化与致癌驱动基因AR、MYC和ERG RNA表达相关的基因间区域。最后，研究表明在癌症进展过程中差异甲基化优先发生在体细胞突变热点和假定的调控区域。这项研究是在转移癌中进行的全基因组、全甲基基因组和全转录组测序的大型综合研究，它全面概述了甲基化在转移性去势抵抗性前列腺癌中的重要调节作用。

据悉，尽管DNA甲基化是基因表达的关键调节剂，但尚未确定转移性癌症的全面甲基化图谱。

附：英文原文

Title: The DNA methylation landscape of advanced prostate cancer

Author: Shuang G. Zhao, William S. Chen, Haolong Li, Adam Foye, Meng Zhang, Martin Sjstrm, Rahul Aggarwal, Denise Playdle, Arnold Liao, Joshi J. Alumkal, Rajdeep Das, Jonathan Chou, Junjie T. Hua, Travis J. Barnard, Adina M. Bailey, Eric D. Chow, Marc D. Perry, Ha X. Dang, Rendong Yang, Ruhollah Moussavi-Baygi, Li Zhang, Mohammed Alshalalfa, S. Laura Chang, Kathleen E. Houlahan, Yu-Jia Shiah, Tomasz M. Beer, George Thomas, Kim N. Chi, Martin Gleave, Amina Zoubeidi, Robert E. Reiter, Matthew B. Rettig, Owen Witte, M. Yvonne Kim, Lawrence Fong, Daniel E. Spratt, Todd M. Morgan, Rohit Bose, Franklin W. Huang, Hui Li, Lisa Chesner, Tanushree Shenoy, Hani Goodarzi, Irfan A. Asangani, Shahneen Sandhu, Joshua M. Lang, Nupam P. Mahajan, Primo N. Lara, Christopher P. Evans, Phillip Febbo, Serafim Batzoglou, Karen E. Knudsen, Housheng H. He

Issue&Volume: 2020-07-13

Abstract: Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes that were detectable only with integrated whole-genome approaches. Notably, we observed that 22% of tumors exhibited a novel epigenomic subtype associated with hypermethylation and somatic mutations in TET2, DNMT3B, IDH1 and BRAF. We also identified intergenic regions where methylation is associated with RNA expression of the oncogenic driver genes AR, MYC and ERG. Finally, we showed that differential methylation during progression preferentially occurs at somatic mutational hotspots and putative regulatory regions. This study is a large integrated study of whole-genome, whole-methylome and whole-transcriptome sequencing in metastatic cancer that provides a comprehensive overview of the important regulatory role of methylation in metastatic castration-resistant prostate cancer. Whole-genome bisulfite sequencing along with whole-genome and transcriptome sequencing of 100 prostate cancer metastases identifies genomic regions that are differentially methylated during disease progression and a novel epigenomic subtype.

DOI: 10.1038/s41588-020-0648-8

Source: https://www.nature.com/articles/s41588-020-0648-8